2-222201817-C-CA

Variant names:

• chr2-222201817-C-CA
• rs368725878
• NM_181458.4:c.1420+126dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_181457.4(PAX3):​c.*106dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 127,078 control chromosomes in the GnomAD database, including 3,188 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.24 (3188 hom., cov: 24)
  • Exomes 𝑓: 0.28 (438 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAX3 NM_181457.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.474
• Publications: 3 publications found

Genes affected

PAX3 (HGNC:8617): (paired box 3) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]

PAX3 Gene-Disease associations (from GenCC):

• craniofacial-deafness-hand syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Waardenburg syndrome type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome type 3

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-222201817-C-CA is Benign according to our data. Variant chr2-222201817-C-CA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334553.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181457.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	NM_181458.4	MANE Select	c.1420+126dupT		intron	N/A	NP_852123.1	P23760-7
	PAX3	NM_181457.4		c.*106dupT		3_prime_UTR	Exon 8 of 8	NP_852122.1	P23760-1
	PAX3	NM_181459.4		c.1420+126dupT		intron	N/A	NP_852124.1	P23760-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	ENST00000392070.7	TSL:1 MANE Select	c.1420+126dupT		intron	N/A	ENSP00000375922.3	P23760-7
	PAX3	ENST00000409551.7	TSL:1	c.1417+126dupT		intron	N/A	ENSP00000386750.3	P23760-6
	PAX3	ENST00000336840.11	TSL:1	c.1174-376dupT		intron	N/A	ENSP00000338767.5	P23760-5

Frequencies

GnomAD3 genomes AF: 0.239 AC: 30384 AN: 127024 Hom.: 3182 Cov.: 24

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.327

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.228

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.275 AC: 329055 AN: 1194964 Hom.: 438 Cov.: 0 AF XY: 0.274 AC XY: 162486 AN XY: 593592

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.228 AC: 6055 AN: 26552

American (AMR) AF: 0.188 AC: 6024 AN: 31962

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 6002 AN: 21596

East Asian (EAS) AF: 0.263 AC: 8888 AN: 33786

South Asian (SAS) AF: 0.273 AC: 19075 AN: 69778

European-Finnish (FIN) AF: 0.243 AC: 9993 AN: 41156

Middle Eastern (MID) AF: 0.263 AC: 948 AN: 3610

European-Non Finnish (NFE) AF: 0.282 AC: 258333 AN: 916568

Other (OTH) AF: 0.275 AC: 13737 AN: 49956

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.239 AC: 30416 AN: 127078 Hom.: 3188 Cov.: 24 AF XY: 0.241 AC XY: 14723 AN XY: 61016

African (AFR) AF: 0.200 AC: 6808 AN: 34002

American (AMR) AF: 0.224 AC: 2751 AN: 12302

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 864 AN: 3076

East Asian (EAS) AF: 0.310 AC: 1400 AN: 4510

South Asian (SAS) AF: 0.312 AC: 1260 AN: 4038

European-Finnish (FIN) AF: 0.250 AC: 1920 AN: 7686

Middle Eastern (MID) AF: 0.321 AC: 79 AN: 246

European-Non Finnish (NFE) AF: 0.252 AC: 14786 AN: 58712

Other (OTH) AF: 0.228 AC: 395 AN: 1736

Alfa AF: 0.0596 Hom.: 110

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Craniofacial-deafness-hand syndrome (1)
-	-	1	not provided (1)
-	1	-	Waardenburg syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368725878; hg19: chr2-223066536; COSMIC: COSV60585860; COSMIC: COSV60585860;